Progression Of Chronic Renal Disease Research Articles

The role of nuclear receptors in the kidney in obesity and metabolic syndrome

Nuclear receptors are ligand-activated transcriptional regulators of several key aspects of renal physiology and pathophysiology. As such, nuclear receptors control a large variety of metabolic processes, including kidney lipid metabolism, drug clearance, inflammation, fibrosis, cell differentiation, and oxidative stress. Derangement of nuclear receptor regulation, that is, mainly due to obesity may induce metabolic syndrome, may contribute to the pathogenesis and progression of chronic renal disease and may result in end-stage renal disease. This places nuclear receptors at the forefront of novel therapeutic approaches for a broad range of kidney disorders and diseases, including glomerulosclerosis, tubulointerstitial disease, renal lipotoxicity, kidney fibrosis, and hypertension. This review focuses on the importance of the transcription factors peroxisome proliferator-activated receptor alpha, peroxisome proliferator-activated receptor beta, peroxisome proliferator-activated receptor gamma, liver X receptors, farnesoid X receptor, and the pregnane X receptor/steroid and xenobiotic receptor (PXR) on the physiology and pathophysiology of renal diseases associated with obesity and metabolic syndrome.

Renal BOLD-MRI and assessment for renal hypoxia

Renal tissue hypoxia may play a major role in the progression of chronic renal disease. Michaely et al. used blood oxygen level-dependent magnetic resonance imaging to test this hypothesis. They found no relationship between renal oxygenation and stage of chronic kidney disease (CKD). However, renal tissue oxygenation may be related not only to the severity of renal disease but also to its underlying etiology. This added complexity confounds interpretation of data obtained from subjects with CKD due to multiple etiologies.

Screening for Microalbuminuria in HIV-Positive Children in Enugu

Background. Human immunodeficiency virus associated nephropathy (HIVAN) is a rapidly progressive chronic renal parenchymal disease that occurs in HIV-infected individuals and manifests commonly as proteinuria, which is preceded by microalbuminuria (MA). This clinical entity is defined as a spot urine albumin of 20–200 mg/L. Objectives. To determine the prevalence of microalbuminuria in HIV positive children in UNTH, Enugu and compare it with that of HIV-negative children. Methods. A total of 154 HIV positive children aged 18 months to 14 years and 154 HIV-negative children of corresponding attributes were screened for microalbuminuria, using Micral test II strip which has a sensitivity of 90–99%. Results. No child among the groups (HIV positive and negative) had microalbuminuria. Majority (96.0%) of HIV-positive children had nonadvanced HIV disease at the time of the study (P = 0.00). About 77.3% were using HAART (P < 0.0001), the mean CD4 cell count of the subjects was 709.2 ± 443.9 cells/mm3; while 78.0% had nonsevere immunosuppression (P = 0.00). Furthermore, HIV-positive children with severe immunosuppression were younger and had shorter duration of treatment. Conclusion. Microalbuminuria may not be very common in Nigerian children irrespective of their HIV status.

Oxidative damages in tubular epithelial cells in IgA nephropathy: role of crosstalk between angiotensin II and aldosterone

BackgroundInhibition of the renin-angiotensin-aldosterone system (RAAS) slows down the progression of chronic renal diseases (CKD) including IgA nephropathy (IgAN). Herein, we studied the pathogenetic roles of aldosterone (Aldo) in IgAN.MethodsHuman mesangial cells (HMC) was activated with polymeric IgA (pIgA) from IgAN patients and the effects on the expression of RAAS components and TGF-β synthesis examined. To study the roles of RAAS in the glomerulotubular communication, proximal tubular epithelial cells (PTEC) was cultured with conditioned medium from pIgA-activated HMC with eplerenone or PD123319, the associated apoptotic event was measured by the generation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS).ResultsPolymeric IgA up-regulated the Aldo synthesis and aldosterone synthase expression by HMC. The release of TGF-β by HMC was up-regulated synergistically by AngII and Aldo and this was inhibited by incubation of HMC with losartan plus eplerenone. Cultured PTEC express the mineralocorticoid receptor, but not synthesizing aldosterone. Apoptosis, demonstrated by cleaved PARP expression and caspase 3 activity, was induced in PTEC activated by conditioned medium prepared from HMC cultured with pIgA from IgAN patients. This apoptotic event was associated with increased generation of NADPH oxidase and ROS. Pre-incubation of PTEC with PD123319 and eplerenone achieved complete inhibition of PTEC apoptosis.ConclusionsOur data suggest that AngII and Aldo, released by pIgA activated HMC, served as mediators for inducing apoptosis of PTEC in glomerulo-tubular communications. Crosstalk between AngII and Aldo could participate in determining the tubular pathology of IgAN.

Nutrition and chronic kidney disease

The incidence of malnutrition disorders in chronic kidney disease (CKD) appears unchanged over time, whereas patient-care and dialysis techniques continue to progress. Despite some evidence for cost-effective treatments, there are numerous caveats to applying these research findings on a daily care basis. There is a sustained generation of data confirming metabolic improvement when patients control their protein intake, even at early stages of CKD. A recent protein-energy wasting nomenclature allows a simpler approach to the diagnosis and causes of malnutrition. During maintenance dialysis, optimal protein and energy intakes have been recently challenged, and there is no longer an indication to control hyperphosphatemia through diet restriction. Recent measurements of energy expenditure in dialysis patients confirm very low physical activity, which affects energy requirements. Finally, inflammation, a common state during CKD, acts on both nutrient intake and catabolism, but is not a contraindication to a nutritional intervention, as patients do respond and improve their survival as well as do noninflamed patients.

Renal glomerular and tubular injury after gastric bypass in obese rats

Objective Roux-en-Y gastric bypass (RYGB) surgery is the most common surgical intervention for long-term weight loss in morbidly obese patients. By decreasing obesity-associated hyperfiltration, diabetes, and hypertension, RYGB is touted to stabilize, if not prevent, progression of chronic renal disease. To test this, the renal histology of diet-induced obese rats that underwent RYGB surgery was compared with that of pair-fed and sham obese controls. Methods Sprague-Dawley rats, fed a high-fat, low-oxalate diet to induce gross obesity, were randomized to RYGB ( n = 6), gastrointestinal-intact sham-operated obese controls (sham, n = 4), or gastrointestinal-intact sham-operated obese pair-fed controls (fed, n = 8). Daily body weight and food intake were recorded. On postoperative day 42, renal histology and immunohistochemistry were examined. Renal pathology was assessed by a categorical glomerular lesion score and a quantitative glomerular/tubular scoring system by experienced veterinary pathologists. Osteopontin and ED-1 (monocyte/macrophage cell) stainings were estimated by the percentage of stained area and the number of counted cells/high-power field, respectively. Results Compared with sham and fed controls, RYGB rats had significant decreases in body weight ( P < 0.001), more glomerular lesions ( P = 0.02), and received higher glomerular and tubular lesion scores ( P < 0.01). RYGB rodents had significantly stronger staining for osteopontin within the inner medullary region ( P < 0.005) and ED-1 within the outer medullary region ( P < 0.02) compared with sham and fed controls. Conclusion In this diet-induced obese rat model, RYGB is associated with chronic glomerulosclerosis and tubulointerstitial nephritis, confirmed by histology and immunohistochemistry. Prospective studies to better define the injurious mechanisms in this model are underway.

Chronic nicotine exposure exacerbates acute renal ischemic injury

Recent epidemiological reports showed that smoking has a negative impact on renal function and elevates the renal risk not only in the renal patient but perhaps also in the healthy population. Studies suggested that nicotine, a major tobacco alkaloid, links smoking to renal dysfunction. While several studies showed that smoking/chronic nicotine exposure exacerbates the progression of chronic renal diseases, its impact on acute kidney injury is virtually unknown. Here, we studied the effects of chronic nicotine exposure on acute renal ischemic injury. We found that chronic nicotine exposure increased the extent of renal injury induced by warm ischemia-reperfusion as evidenced by morphological changes, increase in plasma creatinine level, and kidney injury molecule-1 expression. We also found that chronic nicotine exposure elevated markers of oxidative stress such as nitrotyrosine as well as malondialdehyde. Interestingly, chronic nicotine exposure alone increased oxidative stress and injury in the kidney without morphological alterations. Chronic nicotine treatment not only increased reactive oxygen species (ROS) production and injury but also exacerbated oxidative stress-induced ROS generation through NADPH oxidase and mitochondria in cultured renal proximal tubule cells. The resultant oxidative stress provoked injury through JNK-mediated activation of the activator protein (AP)-1 transcription factor in vitro. This mechanism might exist in vivo as phosphorylation of JNK and its downstream target c-jun, a component of the AP-1 transcription factor, is elevated in the ischemic kidneys exposed to chronic nicotine. Our results imply that smoking may sensitize the kidney to ischemic insults and perhaps facilitates progression of acute kidney injury to chronic kidney injury.

Capillary rarefaction, hypoxia, VEGF and angiogenesis in chronic renal disease

Tubulointerstitial hypoxia and peritubular capillary rarefaction are typical features of chronic progressive renal disease. In response to low oxygen supply, hypoxia-inducible factors (HIFs) are activated but until now, it is unclear if this increased expression leads to a stabilization of the disease process and thus is nephroprotective or contributes to interstitial fibrosis and/or tubular atrophy. This duality has also been described as far as vascular endothelial growth factor (VEGF), one of the major target genes of HIFs, is concerned. On the one hand, neoangiogenesis driven by VEGF, if intact, ameliorates hypoxia, on the other, VEGF is a potent pro-inflammatory mediator and neoangiogenesis, if defective because interference by other pathologies exaggerates injury. In summary, experimental data support the idea that dependent on timing and predominant pathology, hypoxia counter-regulatory factors exert beneficial or undesirable effects. Thus, before their therapeutic potential can be fully explored, a better way to characterize the clinical and pathophysiological situation in an individual patient is mandatory.

Obesity in renal failure – Health or disease?

The results of numerous investigations on the impact of obesity on renal insufficiency conducted in recent years introduce certain dilemmas about their mutual agreement. Some studies suggest that obesity is negatively correlated with the terminal phase of renal failure. On the other hand, other research has shown that reducing the index of body weight of patients with renal disease improves glomerular filtration. Even more confusion comes from findings indicating that metabolic syndrome in non-diabetic renal disease sufferers increases the risk of occurrence and progression of chronic renal disease. However, some research results suggest that obesity is positively correlated with survival of patients on dialysis, i.e., the higher the index of body weight the lower the mortality rate, especially with extremely obese patients. Reverse epidemiology is a term for the medical hypothesis which holds that the influence of obesity and high body weight indexes may be protective and associated with greater survival of obese patients on haemodialysis. A high serum creatinine concentration is a direct consequence of low rates of glomerular filtration and is inversely correlated with mortality rate. However, observations that high creatinine concentrations before haemodialysis treatment are a predictor of survival may be explained by the fact that they are also the direct consequence of increased muscle mass and a higher dietary protein intake. Thus, improvement of their nutritive state might delay progression and diminish the complications expected for patients suffering from kidney insufficiency. The requirements for daily protein intake by dialysis patients are not clear enough, while a hyperprotein diet may be a significant source of uraemic toxins, phosphate and H(+)-ion, which would be detrimental for their health. Some research has indicated that obesity of dialysis patients is not linked to increased risk of cardiovascular diseases in contrast to the general population. On the other hand, a low body mass index and additional parameters of malnutrition are strong independent indicators of mortality rate in dialysis patients. Although, there is a substantial amount of data that support a protective role for obesity, some authors question the existence of the obesity paradox. They do not oppose the results of that research, but suggest that obese individuals are actually protected in the short-term while later on they are liable to higher mortality risks than people of normal body weight. The role of obesity is undisputed as a significant mortality factor in the general population. Nevertheless, some well-designed studies have confirmed that obesity has a protective influence on patients treated by chronic dialysis procedures. This is not to suggest that obesity is recommended as a model for a higher survival rate in those patients, but the role of 'uraemic adipose tissue' and probable additional factors that might result in a lower mortality rate should be considered.

Nutritional Considerations in Kidney Disease: Core Curriculum 2010

Nutritional Considerations in Kidney Disease: Core Curriculum 2010

Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR

Metabolic acidosis often accompanies low glomerular filtration rate and induces secretion of endothelin, which in turn might mediate kidney injury. Here we tested whether treatment of metabolic acidosis in patients with low glomerular filtration rate reduced the progression of kidney disease. Fifty-nine patients with hypertensive nephropathy and metabolic acidosis had their blood pressure reduced with regimens that included angiotensin-converting enzyme inhibition. Thirty patients were then prescribed sodium citrate, and the remaining 29, unable or unwilling to take sodium citrate, served as controls. All were followed for 24 months with maintenance of their blood pressure reduction. Urine endothelin-1 excretion, a surrogate of kidney endothelin production, and N-acetyl-beta-D-glucosaminidase, a marker of kidney tubulointerstitial injury, were each significantly lower, while the rate of estimated glomerular filtration rate decline was significantly slower. The estimated glomerular filtration rate was statistically higher after 24 months of sodium citrate treatment compared to the control group. Hence it appears that sodium citrate is an effective kidney-protective adjunct to blood pressure reduction and angiotensin-converting enzyme inhibition.

Changes in Serum and Renal Vitamin E Levels in Deoxycorticosterone Acetate–Salt Hypertensive Rats

Hypertension is an important risk factor for the progression of chronic renal disease, which may result in the development of end-stage renal disease. Since reactive oxygen species are implicated in the induction of hypertension, antioxidants have been used to reduce blood pressure and renal impairment in animal models and in human hypertension. However, the available data are not conclusive. To investigate oxidative stress in hypertension, we evaluated renal and serum vitamin E levels as the most effective antioxidant to reduce lipid peroxidation by high-performance liquid chromatography among rats subjected to deoxycorticosterone acetate (DOCA)-salt treatment for 4 weeks. Renal levels of malondialdehyde (MDA) as a marker of cell lipid peroxidation were also assayed in treated rats. Systolic blood pressure (SBP) was measured in conscious rats by the tail-cuff method using a PowerLab/4sp data acquisition system. SBP increased significantly in DOCA-salt-treated rats compared to the sham group after 4 weeks of treatment. Serum vitamin E levels were significantly lower and renal MDA concentrations significantly higher in treated compared to sham rats. However, renal vitamin E levels were also significantly higher among treated compared to sham rats. Decreased plasma vitamin E levels and increased renal MDA levels show systemic and local oxidative stress in DOCA-salt-treated rats. However, the higher renal vitamin E level suggested a local compensatory mechanism. Vitamin E administration might be appropriate, as significant decreases in vitamin E levels were observed in the serum of DOCA-salt-treated rats.

Contribution of Hypoxia inducible factor‐1α to the profibrotic action of angiotensin II in cultured renal medullary interstitial cells

Hypoxia inducible factor (HIF)‐1α has been reported to promote fibrogenesis during the progression of chronic renal diseases. Although angiotensin II (ANG II) was shown to increase HIF‐1α levels in various renal cells, the role of HIF‐1α in ANG II‐induced profibrotic effect has not been determined. The present study was designed to test the hypothesis that HIF‐1α mediates profibrotic effect of ANG II. In cultured renal medullary interstitial cells (RMICs), ANG II (10−6 M) treatment for 20 hours doubled HIF‐1α mRNA levels, which was accompanied by the upregulation of proliferating cell nuclear antigen (PCNA), collagen I/III and tissue inhibitor of metalloproteinases (TIMP)‐1 by 69%, 65% and 26%, respectively. HIF‐1α siRNA decreased HIF‐1α mRNA levels by 60% and completely blocked ANG II‐induced increases in PCNA, collagen and TIMP‐1. Since transdifferentiation is implicated in ANG II‐induced renal tubulointerstitial injury, we also detected the expression of vimentin, a marker of transdifferentiation. It was demonstrated that HIF‐1α siRNA also abolished ANG II‐induced elevation of vimentin mRNA. Our data suggest that HIF‐1α may mediate ANG II‐induced renal fibrotic injury through activation of cell transdifferentiation. (Supported by NIH grant DK54927 and HL89563)

Angiogenesis in the kidney: a new therapeutic target?

The prevalence of chronic kidney disease has been growing consistently for the past decades. Renal failure is often associated with defective angiogenesis, and recognition of the contribution of the renal microcirculation to the progression of chronic renal disease may aid in the development of therapeutic interventions. Intra-renal proliferation, remodeling, and/or rarefaction of microvessels in response to injury can all aggravate nephron damage, and experimental evidence suggests that they may constitute the early steps in the complex pathways involved in progressive renal injury. Recent studies showed the benefits of targeted interventions deemed to promote neovascularization (e.g. progenitor cells, growth factors) on the ischemic myocardium and brain and in a few models of renal disease. Evidence of aberrant renal microvascular architecture in various forms of renal disease provides the impetus to attempt modulating the renal microcirculation to interfere with the disease process. Targeted interventions to preserve the renal microcirculation may not only decrease the evolving injury in renal vascular disease but also potentially constitute a coadjuvant intervention to become part of a comprehensive management plan to improve the success of parallel strategies to preserve renal function, such as revascularization.

The effect of low-protein diet supplemented with ketoacids in patients with chronic renal failure

It is known that dietary protein restriction slows the progression of chronic renal disease. If daily protein intake is less than 0.5-0.6 g/kgbw, the diet has to be supplemented with essential aminoacids/ketoacids. In this study the authors evaluate the long-term effect of low-protein diet supplemented with ketoacids on the progression of chronic renal failure, calcium and phosphorus metabolism, nutritional status, the compliance of patients and the permanent dietary education for the compliance. 51 predialysis patients have been treated with ketoacids supplemented low-protein diet during 12-57 months (mean treatment period: 26 months). Serum creatinine raised from 349.72+/-78.04 micromol/l to 460.66+/-206.66 micromol/l (27 micromol/l/year or 2.3 micromol/l/month), glomerular filtration rate (GFR) decreased from 21.52+/-7.84 ml/min to 18.22+/-7.76 ml/min (0.83 ml/min/year or 0.07 ml/min/month). The slope of 1/serum creatinine versus time was 0.0018 by linear regression analysis. Serum parathormon decreased significantly, but serum calcium and phosphorus did not change. Nutritional status of patients did not change significantly during the follow-up period. Protein intake decreased significantly and remained at this lower level during the treatment period. According to results: low-protein diet supplemented with ketoacids was effective in slowing progression of chronic renal failure, decreased PTH, did not change nutritional status. With permanently and good education it was possible to keep patients on low-protein diet for a long period.

Comparison of various methods of glomerular filtration rate measurements in children

Purpose : Glomerular filtration rate (GFR) is a fundamental parameter in assessing renal function and predicting the progression of chronic renal disease. Because the use of serum creatinine has several disadvantages, many studies have investigated the use of cystatin C for estimating GFR. We compared creatinine clearance and GFR with formulas using serum creatinine and cystatin C. Methods : We retrospectively analyzed 211 patients with various renal diseases and classified them into two groups according to creatinine clearance (Group 1: CrCl >90 mL/min/1.73m2, Group 2: CrCl

Hereditary and acquired complement dysregulation in membranoproliferative glomerulonephritis

Membranoproliferative glomerulonephritis (MPGN) is a chronic progressive renal disease that is diagnosed on the basis of renal histological features. Several MPGN subtypes have been defined by the localization and composition of glomerular deposits (electron dense, Ig and C3). MPGN II or dense deposit disease (DDD) which is defined by the occurrence of electron dense deposits within the lamina densa of the glomerular basement membrane (GBM) is strongly associated with dysregulation of the alternative complement pathway (AP). However, C3 Nephritic Factor (C3NeF), an autoantibody against the alternative C3 convertase C3bBb, and mutations in regulatory proteins of the AP have also been identified in other subtypes of MPGN and even in glomerulonephritis with mesangial C3 deposits. Clinically, MPGN is characterized by proteinuria (up to nephrotic range) and hypertension, frequent progression to end-stage kidney disease and disease recurrence after renal transplantation. The age of onset varies from childhood to adulthood. In the following we will review our current knowledge of pathogenesis of MPGN and will present a novel classification system of the disease based on pathogenesis rather than on morphology. A better understanding of the pathogenesis of MPGN is crucial for the development of novel, specific treatment strategies.

One-year follow-up of renal function in endemic nephropathy families

Endemic nephropathy is familial, chronic tubulointerstitial disease with an insidious onset and asymptomatic, slow progressive course. The present study was undertaken with the aim to find out whether new persons with renal disorders can be detected among members of endemic families in the village of Sopić (Kolubara River region, Serbia). The study involved 44 members of five endemic families without history of renal disorders. Objective survey and laboratory analyzes that enabled determination of kidney functions (creatinine clearance, proteinuria, urine specific gravity and osmolality, fractional sodium excretion (FENa), the rate of tubular phosphate reabsorption (TRP), urine N-acetil-D-glycosaminidase and intestinal alkaline phosphatase) were done in all examined persons three times during the 6-month intervals. At the first examination, hypertension was detected in 23 (52%) person, decreased creatinine clearance in two and proteinuria in 10 persons included in the study. In addition, proteinuria and tubular disorders were detected in 6, hypertension, proteinuria and/or tubular disorders in 9 persons. The analysis of the results obtained by three check-ups undertaken during one year showed that proteinuria and tubular disorders appeared intermittently in half of the examined endemic family members. All persons with detected renal disorders required further examination in order to establish accurate diagnosis of renal disease. Three check-ups performed at six-month intervals in the members of five endemic families detected various renal disorders including renal hypofunction. Regular systematic check-ups of endemic families could enable early detection of the disease and early initiation of measures for slowing down chronic renal disease progression.

Suppression of renin–angiotensin gene expression in the kidney by paricalcitol

The renal renin-angiotensin system plays a major role in determining the rate of chronic renal disease progression. Treatment with activators of the vitamin D receptor retards the progression of experimental chronic renal disease, and vitamin D is known to suppress the renin-angiotensin system in other organs. Here we determined if the beneficial effects of paricalcitol (19-nor 1,25-dihydroxyvitamin D(2)) were associated with suppression of renin-angiotensin gene expression in the kidney. Rats with the remnant kidney model of chronic renal failure (5/6 nephrectomy) were given two different doses of paricalcitol thrice weekly for 8 weeks. Paricalcitol was found to decrease angiotensinogen, renin, renin receptor, and vascular endothelial growth factor mRNA levels in the remnant kidney by 30-50 percent compared to untreated animals. Similarly, the protein expression of renin, renin receptor, the angiotensin type 1 receptor, and vascular endothelial growth factor were all significantly decreased. Glomerular and tubulointerstitial damage, hypertension, proteinuria, and the deterioration of renal function resulting from renal ablation were all similarly and significantly improved with both treatment doses. These studies suggest that the beneficial effects of vitamin D receptor activators in experimental chronic renal failure are due, at least in part, to down-regulation of the renal renin-angiotensin system.

Endothelial injury due to eNOS deficiency accelerates the progression of chronic renal disease in the mouse

The vascular endothelium expresses endothelial nitric oxide synthase (eNOS) that generates nitric oxide (NO) to help maintain vascular integrity due to its anti-inflammatory, antiproliferative, and antithrombogenic effects. Pharmacological blockade of NO production has been shown to exacerbate renal injury in chronic renal disease and induces endothelial cell loss. However, pharmacological inhibition of NO nonspecifically blocks other types of NOS and therefore does not define the specific role of eNOS in kidney disease. We hypothesized that a lack of endothelial eNOS can induce a loss of glomerular and peritubular capillary endothelium and exacerbate renal injury in progressive renal disease. We tested out this hypothesis using remnant kidney (RK) in eNOS knockout (eNOS KO) mice. Systolic blood pressure was significantly higher, and renal function was worse in RK-eNOS KO mice compared with those in RK-C57BL6 mice. eNOS deficiency resulted in more severe glomerulosclerosis, mesangiolysis, and tubular damage. Glomerular and tubular macrophage infiltration and collagen deposition were also greater in RK-eNOS KO mice. Renal injuries in the RK-eNOS KO mice were accompanied by a greater loss of endothelial cells that was shown to be due to both a decrease in endothelial cell proliferation and an increase in apoptosis. A lack of eNOS accelerates both glomerular and tubulointerstitial injury with a loss of glomerular capillaries and peritubular capillaries. Impaired endothelial function is likely a direct risk factor for renal disease.